Measles, a highly infectious viral disease is the next target for eradication following poliovirus. Decades of experience with highly effective vaccination has invigorated us to take on this virus. The task is not only Titanic but is laced with intricate issues. Recently, an outbreak of fever with rash occurred on a tertiary care teaching hospital campus and was confirmed serologically as measles outbreak by IgMELISA. Therefore, we searched the literature related to outbreaks, transmission of the measles virus, age groups involved, vaccination strategies, vaccination failure and epidemiological features of the disease and reviewed the possible reasons for such outbreaks and problems in the global eradication of the virus.

Measles is a highly infectious viral illness associated with fever and rash. The most common age group affected is children under 5 years of age. It may lead to serious complications including pneumonia and encephalitis and may lead to death.[1] Subacute sclerosing panencephalitis is not infrequent even in India.[2] The endemicity of measles is persistent in advanced, developing and underdeveloped countries in spite of the availability of vaccine for over 60 years. The resurgence of measles was noted in Granada since 2009. Of the 53 European Region States, 36 reported measles outbreaks in 2011, in spite of having a very good vaccination program.[3] Over a span of 20 years from 1963 the reported number of measles cases in the US dropped from 500,000 to <1500 per year. Because of excellent vaccine coverage, endemic transmission of measles was declared eliminated from the United States in 2000.[4] However, the resurgence of this infection was seen from 1989, and around 120 deaths were reported till 1991. On genotyping, it was found that most of the virus isolates in this phase were genetically different from the vaccine virus.[5] This observation may influence the measles elimination initiative by the World Health Organization (WHO).

The measles virus (MeV) is serologically monotypic, but genotyping confirms eight clades (A–H). The clades are further subdivided into 23 genotypes, and the number is likely to increase as more geographic areas will be brought under investigation. The WHO is patronising genotyping work through Measles and Rubella Laboratory Network and a significant amount of information on the distribution of the clades worldwide has been generated.[6] The identification of new genotypes is the result of technological advances rather than the generation of newer genotypes. The vaccine in current use is prepared from clade A. The immune response to this vaccine strain is protective against infection from all the clades. Although sera from vaccinated individuals neutralise all the clades, the efficacy varies from clade to clade. It may be said that the level of protection offered by this vaccine varies from genotype to genotype. Genetic drift in the H protein is noted. The efficiency of sera for neutralisation of wild-type MeV was assessed. It was found that there is no association between the genotypes and resistance to neutralisation.[6],[7],[8]

During measles epidemic, children having fever and rash are not usually subjected to laboratory evaluation. When patients belonging to other age groups present with fever and rash, the diagnosis of causative agent heavily depends on laboratory investigations. The non-classic cases of measles in vaccinated subjects may never raise suspicion of measles. Transmission from non-classic cases of measles is known.[9],[10] The consequences of possible spread from such cases, and particularly from cases among health-care workers, puts tremendous pressure on those who are responsible for outbreak control. Infected health-care workers, because of their non-classic presentation, may transmit this highly infectious pathogen to immunologically challenged patients, for example, diabetics, those having malignant conditions, antenatal women, etc.[11],[12]

In the present review the continued existence of MeV even in highly vaccinated populations, implications of outbreaks and relevance of laboratory support are discussed with a brief report on our recent experience of measles outbreak among medical students.

~ Outbreak Report

SDM College of Medical Sciences and Hospital, Dharwad is situated in North Karnataka, India. The institute has five hostel buildings on the campus and is occupied by 1085 students. The outbreak began around October 7, 2013. Approximately, twenty students were affected in this outbreak. The students were all from undergraduate MBBS classes except one nursing student and one MBBS intern. Male students were 12 in number while the number of female students was 8. [Table 1] shows the clinical presentation of the cases. Initially, the students presented to the casualty with complaints of fever with chills and constitutional symptoms. All the twenty students had a fever. With symptomatic medication, the fever subsided. Students continued their daily routine for one or 2 days. The students then started getting sore throat. Most of the students (18) complained severe throat pain. Some of the students developed ulcers resembling aphthous-like ulcers on pharyngeal region, tongue and palate. The ulcers were painful, with burning sensation and students were unable to eat anything. Some students developed conjunctival suffusion and moderate to severe injection of conjunctiva, itching and discharge. Thirteen students developed cough. Two students gave a history of continuous cough over one entire night. In the others, the cough was there but was not so severe. The students then started getting a high fever. The fever ranged from 101°F to 103° F. On 4th–5th day of the illness students started getting skin rashes [Figure 1] and [Figure 2]. The rashes began to appear on forehead and then gradually spread downwards over chest, extremities and trunk. Both the upper and lower extremities were involved. The rash was macular in nature. The rash was non-itching or burning except only in a few cases. The rash started disappearing by 3rd or 4th day of eruption. The palms and soles were also involved in many cases. The fever subsided in most cases when the progression of rash stopped. Seven students had gastrointestinal (GI) symptoms. They had severe vomiting, cramps and watery diarrhoea. Supportive treatment took 3 days for recovery from GI symptoms. All the students recovered and were discharged from the hospital. A few had a bout or two of watery, loose motions at the end of the illness. No student showed hepatomegaly or splenomegaly. No student had leucocytosis. The severity of the illness varied from moderate to severe. The total episode lasted for an average of 8 days.

Most were treated with antipyretics, antibiotics and supportive therapy

The serological tests for dengue (NS1, IgM and IgG by immunochromatography), malaria (quantitative buffy coat, peripheral smear and antigen detection), leptospira IgM/IgG and Weil–Felix test were negative in all the cases

Haematological picture was not specific. The platelet counts were within normal limits

Monocyte counts ranged from 5% to 18%

No atypical cells or bands were seen

None of the cases were treated with ampicillin

No postgraduate student or any other staff members including treating doctors were affected in this outbreak.

Blood samples were collected from 26 students of which 12 were in convalescence phase and were admitted at that moment at our hospital. Remaining 14 samples were collected from close contacts of the cases. Blood samples from other infected students could not be collected as some of them had left for hometown for parental care and rest. The serum was separated aseptically. Each serum sample was aliquoted into two sterile screw capped tubes, and two sets of the samples were prepared. One set was sent to National Institute of Virology, Pune (NIV) and the second, to National Institute of Mental Health and Neurosciences, Bengaluru (NIMHANS). The samples were carried on ice in vaccine carriers. The samples were subjected to ELISA test for detection of IgM antibodies against measles and rubella at NIV (Siemens Healthcare Diagnostics Products GmbH, Germany) and for molecular identification of common viral agents causing fever and rash at NIMHANS, Bengaluru.

Observations

As shown in [Table 2], 7 out of 12 samples from cases were positive for IgM antibodies against MeV, and two samples showed equivocal titres. None of the samples was positive for IgM antibodies against rubella virus

Of the 14 samples from close contacts, no sample was positive for antibodies against either MeV or rubella virus except one sample showing equivocal result for IgM antibody against MeV

None of the samples was positive for molecular identification of the six causative agents tested by NIMHANS, Bengaluru (telephonic communication).

The MeV is one of the important viruses having exclusive human infectivity. Fever and maculopapular rash and at least one of the symptoms such as cough, coryza or conjunctivitis are important for clinical diagnosis. Transmission occurs from human to human, but carrier state is questionable. Long-term asymptomatic transmission of virus is unlikely. The transmissibility is so alarming that there is a concern about this virus being used as a biological weapon.[13],[14]

During the pre-vaccine era, measles was confined to paediatric age group as the infection was seen to provide lifelong immunity. The current vaccine for this most highly contagious human infection was developed 50 years ago. Since the introduction of measles vaccine in 1963, the incidence in the developing nation or developing country dropped drastically. Vaccination was found to be very effective. The policy makers are now contemplating to target measles as the next pathogen to eradicate following poliovirus.[15],[16],[17] However, the present vaccine does not offer complete protection assurance, and the limitations are evident now. Newer strains show epitopes that are not shared by the vaccine strains. Variations in the efficacy of neutralisation in the vaccinated individuals against wild MeV has been reported.[7],[18] In spite of the availability of vaccine, more than 20 million measles cases are reported every year all over the globe. In 2010, alone 139,300 deaths due to measles were reported underlining the public health importance of this infection.[19]

The occurrence of cases of measles is being noted, not only in the developing or underdeveloped countries but also in the developed world including America, Europe, New Zealand, Spain, France, Germany, the UK, Romania and a large number of other European countries and the phenomenon continues.[20] The year 2014 saw the largest number of measles cases in the United States since measles elimination was documented in 2000.[21],[22] It is being observed all over the Europe and in other developed countries that measles is appearing in the form of outbreaks. It is important to note that the outbreaks are seen even in well-vaccinated communities and individuals.

It is clear that Measles is re-emerging. The Health Protection Agency of England and Wales has declared this infection to be endemic.[14] Vaccine, the most important intervention in the transmission of measles, is failing to confer enough immunity to public and is evident by the fact that around 30,000 cases occurred in Europe in 2011. Alarming number of cases in previously vaccinated subjects have been observed in properly vaccinated populations.[23],[24] A very high proportion of 47% cases in pre-vaccinated school children is reported from the US.[25] Poland et al. (1997) found that the seroconversion after single dose measles vaccination was only 81.5%.[26] It is also shown that around 2%–10% subjects vaccinated with two doses of measles vaccine fail to develop protective immunity. Two-dose vaccination strategy was introduced in India in 2010.[27] The protection level varies from individual to individual, and also, the antibody levels wane over time. Studies have shown that response to measles vaccine varies in people and is the result of the human leucocyte antigen (HLA) genotypes, single nucleotide polymorphisms modifying the cytokine receptors and CD46 membrane receptors. These genetic factors are the cause of insufficient herd immunity in the vaccinated community leading to higher than expected vaccine failures.[14],[28],[29],[30]

~ Genotypes of Measles Virus

The resurgence of measles has made us to realise the need for molecular characterisation of wild-type MeV. Nucleotide sequences of haemagglutinin (H) and nucleoprotein (N) genes are used for typing the strains. These are the most variable of the six genes of this virus. The 450 bp stretch at the COOH terminus of the N gene shows the highest variability.[5] With the advent of genotyping, researchers quickly realised that 'genotype A' was not the only genotype prevalent in the pre-vaccine era.

There is a need to develop next-generation vaccines. MeV has eight clades from A to H which are further subdivided. The vaccine has been prepared from the Edmonston strain that belongs to clade A. Vaccination generates antibodies that protect against all the clades. However, the degree of protection offered by the antibodies stimulated by one clade may not be uniform against all the other clades.[5],[8] The immediate post-vaccination spread of measles by different clade has been reported. This observation signifies the variability of neutralising potential of antibodies generated by one clade against other clades. This could be an important phenomenon for continued endemicity of measles, as 96%–98% population needs to be immune to abort endemicity of MeV.[31],[32] Viral RNA polymerases are deficient in proofreading during replication resulting in higher mutation rates in viral genome seen in these viruses.[33] In India, the genotype D4 is distributed widely with co-circulation of genotype D8 and D7 has also been occasionally reported.[34],[35] Australia and the US seem to have imported this genotype from India and Bangladesh. Entry of a new MV clade in any population may produce a few clinical or subclinical infections.[5] It is, therefore, important to survey and monitor the circulation of MV clades in any population. Reverse vaccine or genome-based vaccines are being developed to overcome the drawbacks of the existing vaccine. Individual diatheses leading to suboptimal immunogenicity are under investigation. Close positive and negative associations of HLA antigens and immunogenicity have been shown. Lower seroconversion rates are seen in people having B * 8, B * 13, B * 44, DRB1 * 03 and DQA1 * 0201 alleles vis-à-vis class I B * 7, class II DQA1 * 0104 and DPA1 * 0202 alleles show excellent antibody response. Huge throughput technologies have opened new research gates. The ability of the computers to handle, comprehend and analyse huge data is helping systems biology to provide newer insights into vaccinology.[14],[23],[36]

Epidemiological studies with this new tool of genotyping are not easy as the disease is widely distributed worldwide. Often, it produces outbreaks and epidemics in poorly accessible geographical terrains. Collection and transportation of samples in adequately good condition for molecular analysis is a challenge. However, dried blood and dried oral fluids are shown to be useful specimens for genotyping.[37],[38] This should encourage researchers from resource poor settings to conduct epidemiological studies of measles.

~ Measles in Health Care Workers

Medical students are often exposed to patients at an infectious stage of measles during the prodrome or at onset of rash.[39] Persons with adequate protective antibody levels would get a natural booster out of such exposure. Even when they have a clinical infection, the symptoms reported are less severe, modified or non-classic and often of shorter duration compared to primary infection. In the absence of a known exposure to a measles case, the possibility of measles may not be considered in diseased healthcare workers. Therefore, high suspicion, stringent isolation and early diagnosis, are very important to prevent outbreaks. Immuno-colorimetric assay and RT-PCR have been shown to be highly useful for early virological diagnosis of measles.[40] Accidental exposure to a case of measles can transmit the infection, and an infected health-care worker may spark an outbreak. It is known that exposed healthcare workers, such as training medical specialists and other young professionals, are a group considered susceptible to this rapidly transmissible infection especially on account of their age (25–35-year-old).[9],[12],[41]

The students involved in this episode at our institute could not provide an accurate history of vaccination and this phenomenon has been observed by other workers also.[42] None could be related to exposure to a clinically suspected case of measles. Considering their parents' educational and economic background, it is highly likely that most of these students were vaccinated. They hailed from various parts of India. Because of adequate measles vaccination coverage in the population and surroundings where they grew up, these students probably had never encountered wild MeV. They did not get the natural booster from virus circulating in the community, and their immunity probably wanted to suboptimal protective level. Except one nursing student and one internist all the affected were undergraduate medical students. The undergraduate medical students are minimally exposed to clinical cases compared to interns and residents. This group of students, thus, was a susceptible pocket of students. Because of their proximity during daily routine, an infection caught by one might have rapidly spread to others producing this outbreak. The absence of virus circulating in the community diminishes periodic natural boosting altering the paradigm of lifelong immunity after vaccination or disease. Helfand et al., (1998) hypothesise that the rate of non-classic infection is likely to increase as measles control improves in a population because boosting from exposure to wild-type MeV will be rare. This may occur in elderly having no exposure to the virus for a long period.[10]

The rash in this outbreak had the typical progress from head to trunk and then to limbs. An interesting finding was rash on palms and soles which are usually spared in measles rash.[43] Epidemiological pattern of the outbreaks is changing. Most of the outbreaks are found to have involved higher age group subjects, teenagers being more common.

Not receiving vaccination is a major factor predisposing the subjects to measles. It is reported by Navarro et al. that in Granada outbreak, a big proportion of 89% of the cases had not received vaccination.[3] Laboratory testing of serum samples from asymptomatic or mildly ill contacts of a measles case can detect an immunologic response to measles infection. As reported by Helfand et al. many persons who were exposed to a measles case on a 3-day bus trip had a detectable IgM response, regardless of having received previous vaccination or, for some, having a history of natural measles infection.[10] In addition, the titres measured from the exposed persons on the bus in which the measles case travelled were significantly higher than those obtained from persons who travelled on the second bus in the caravan. The clinical presentations of the exposed persons with detectable antibodies and/or measles neutralising antibodies, however, did not meet the measles clinical case definition.

[Table 3] shows the table for statistical analysis of the results. One sample had given equivocal result. Considering the rapidly spreading infectious condition this test result was clubbed with positive results. Fisher's Exact Probability test was applied for the interpretation of the results. This test yielded a P = 0.0008, which confirms this episode to be an outbreak of measles.

Although detection of IgM is the recommended method for measles confirmation, it is an unreliable marker for measles infection in persons with a secondary immune response (SIR). The ability to detect IgM among persons with a SIR following exposure to measles will depend on the magnitude and kinetics of the individual immune response, the timing of the serum sample collection, and the sensitivity of the assay. In addition, because of the rapid escalation of IgG levels, it may not be possible to demonstrate a four-fold rise in IgM titre among SIR cases. However, when clinical samples are collected in timely manner, real-time Reverse transcription-polymerase chain reaction (RT-PCR) testing may detect virus in persons with modified illness. The ability to discern measles infection in persons with a SIR, however, is valuable for surveillance purposes in support of measles eradication efforts. Cases are reported where antibody response could not be demonstrated but the infection was diagnosed by molecular method.[3],[10],[29],[44],[45] Modified measles infections may also resemble other rash illnesses including rubella, dengue or Parvovirus B19 and can be confusing.[45] Dual infections with measles and rubella are also known.[47] PCR is capable of detecting asymptomatic measles infection. Reliance on the absence of IgM to rule out a case may be unjustified under these circumstances, and use of RT-PCR in suspected cases, especially in vaccinated contacts presenting non-classically is definitely warranted.[48] Immunity to measles may not be absolute but, depending on the levels of pre-existing antibody, reflect a continuum of clinical illness. Not only the level of pre-existing antibody but also the intensity of exposure (i.e., the dose of virus) is an important risk factor for breakthrough infection. The absence or reduced severity of respiratory symptoms, particularly a cough, may result in lower infectivity relative to a classic measles infection.[46]

~ Achieving Optimum Community Immunisation

Although elimination of MeV is being considered the next possible goal, it seems to be a distant reality. Unfortunately, anti-vaccination campaigns for various reasons including religious or ideological beliefs are creating obstacles in the control of this highly infectious virus. Resistance to vaccination creates population groups susceptible to measles. Coercive measures may be necessary to control outbreaks in certain situations.[49] In some such situations, legal help was sought to vaccinate the unvaccinated children to protect other children. In some countries, a proof of vaccination of the child is a mandatory prerequisite for school entry. Outbreaks of measles due to failure to vaccinate susceptible populations are reported. A phenomenon designated as a historical pocket of susceptible adults is described. This refers to unvaccinated adults born before the beginning of vaccination. Because the good vaccination coverage rapidly interrupted the circulation of the virus at the start of vaccination regimen in 1984, this age group people neither received vaccine nor had any natural exposure to MeV.[3],[5]

The only way to monitor the success of immunisation is genotyping. Genotyping studies revealed that multiple serotypes were active in outbreaks in Romania from 2004 to 2012. There is a strong need to study the molecular epidemiology of measles in various geographical regions. This would provide key data or evidence for a need of newer vaccine and whether we need polyvalent vaccine. Do we need different combinations of clades or their subtypes for different geographical areas; would be a key issue if we are contemplating global elimination of measles. The absence of endemic circulation and identification of entry of new genotypes in a population is possible only by genotyping. The absence of transmission for more than 12 months is one of the criteria to define the absence of endemic circulation. However, in well-vaccinated populations also, virus introduced by importation will continue to fuel sporadic outbreaks and epidemics.[50] It is essential to sensitise, train and educate health-care providers to collect specimens and send them to higher centres for molecular analysis.

Because of epidemics and outbreaks, especially in the developing world, the WHO deferred the proposed date for measles from European region to 2015.[51] The South East Asian countries record more than 75% of the global measles deaths, India being the biggest contributor.[27] Under-vaccinated groups in any community are a great nuisance thwarting elimination of measles because of their potential to sustain and propagate the virus within that community.

The important hurdles in the elimination of measles are sub-optimal immunisation in both developing and developed countries, resistance to vaccination on ideological or religious grounds, questionable protection of the vaccine evident by measles cases in partially or fully vaccinated subjects and mobility of the people between endemic and non-endemic areas. In spite of this, the risk analysis shows that there is a low possibility of reintroduction of measles after its eradication.[13] Elimination of measles will need globally coordinated efforts. WHO South-East Asia Region have pledged commitment to eliminate measles by 2020.[27] Local elimination of measles would not be enough to control the infection globally. We do not need an oracle to prophesy that we need to go a long way before we give the Coup de grace to MeV.

~ Conclusion

Global eradication or elimination of measles is possible. A few problems are anticipated in the light of the available evidence. The available vaccine seems to be potent to control the spread of MeV worldwide. The seroconversion attainable with this vaccine may be marginally less than what is necessary to stop the circulation of MeV. Continued research to offer enhanced protection and avert vaccination failures is essential. An alternative vaccine with newer immuno-stimulating modalities such as adjuvants may be required to achieve complete elimination of MeV. The essentiality of public education and commitment on the part of government agencies as well as judiciary cannot be overemphasised.